The DNA genome in the particle of a DNA virus can be double-stranded, single-stranded, or partially double-stranded DNA. Papovaviridae (e.g., papillomaviruses), herpesviridae (e.g., herpes simplex viruses), and adenoviridae (e.g., adenoviruses) contain double-stranded DNA genomes. Some viruses from parvoviridae (e.g., parvoviruses) contain single-stranded DNA as their genomes. Some viruses from hepadnaviridae (e.g., hepatitis B virus) contain partially double-stranded DNA as their genomes, and replicate their genomes through RNA intermediates. In contrast, retroviruses are a family of RNA viruses that replicate through a DNA intermediate. Examples of retroviruses include Moloney murine sarcoma viruses, human T-cell lymphotrophic viruses, human immunodeficiency viruses, and human foamy viruses.
Viruses described above cause a variety of diseases, such as the flu, common cold, herpes, measles, small pox, and encephalitis. Vaccination only offers protection for uninfected individuals for a few viral diseases. Thus, there is a need for identifying therapeutic agents useful for preventing or treating viral infection.
The present invention is based, in part, on the discovery of nucleotide analogs that possess anti-viral activity.
In one aspect, this invention relates purine compounds of formula (I): 
R1 is NH2 or OH; R2 is H or NH2; R3 is H or alkyl; each of m and n, independently, is 1, 2, 3, or 4; X is O, S, or NH; and Y is H, halogen, ORa, P(O)(ORa)2, or P(O)(ORa)(ORb), in which Ra is H, alkyl, aryl, heteroaryl, cyclyl, heterocyclyl, and Rb is 
(referred to as xe2x80x9csugar-A(Rc)xe2x80x94OP(O)(ORd)(ORe)xe2x80x9d hereinafter), wherein A is adenine, guanine, cytosine, uracil, or thymine; Rc is H or OH; Rd is H or alkyl; Re is H, alkyl, or 5-ethylidene-(3,4-dialkoxyl)-furan-2-one; provided that if R1 is NH2, R2 is H; and if R1 is OH, R2 is NH2. Note that the left atom shown in any of the substituted groups set forth above is closest to the purine ring.
Referring to formula (I), a subset of the purine compounds are those in which each of R1 is NH2 and R2 is H. In these compounds, R3 can be H; X can be O; and each of m and n, independently, is 1 or 2. In some embodiments, m is 1, X is O, n is 2, and Y is ORa, in which Ra can be H. In other embodiments, m is 2, X is O, n is 1, and Y is P(O)(ORa)2, in which Ra can be H. In still other embodiments, m is 2, X is O, n is 1, and Y is P(O)(ORa)(ORb), in which Ra can be H, and Rb can be sugar-A(Rc)xe2x80x94OP(O)(ORd)(ORe).
Another subset of the purine compounds of formula (I) are those in which R1 is OH and R2 is NH2. In these compounds, R3 can be H; X can be O; and each of m and n, independently, is 1 or 2. In some embodiments, m is 1, X is O, n is 2, and Y is ORa, in which Ra can be H. In other embodiments, m is 2, X is O, n is 1, and Y is P(O)(ORa)2, in which Ra can be H. In still other embodiments, m is 2, X is O, n is 1, and Y is P(O)(ORa)(ORb), in which Ra can be H, and Rb can be sugar-A(Rc)-OP(O)(ORd)(ORe).
In another aspect, this invention encompasses purine compounds of formula (II): 
R1 is NH2 or OH; R2 is H or NH2; R3 is H or alkyl; each of m and n, independently, is 1, 2, 3, or 4; X is O, S, or NH; and Y is P(O)(ORa)(ORb), in which Ra is H, alkyl, aryl, heteroaryl, cyclyl, heterocyclyl; and Rb is 5-ethylidene-(3,4-dialkoxy)-furan-2-one or sugar-A(Rc)xe2x80x94OP(O)(ORd)(ORe); wherein A is adenine, guanine, cytosine, uracil, or thymine; Rc is H or OH; Rd is H or alkyl; Re is H, alkyl, or 5-ethylidene-(3,4-dialkoxyl)-faran-2-one; provided that if R1 is NH2, R2 is H; and if R1 is OH, R2 is NH2.
Referring to formula (II), a subset of the purine compounds are those in which each of R1 is NH2 and R2 is H. In these compounds, R3 can be H; X can be O; and each of m and n, independently, is 1 or 2. In some embodiments, m is 2, X is O, n is 1, and Y is P(O)(ORa)(ORb), in which Ra can be H, and Rb can be 5-ethylidene-(3,4-dialkoxy)-furan-2-one.
Another subset of the purine compounds of formula (II) are those in which R1 is OH and R2 is NH2. In these compounds, R3 can be H; X can be O; and each of m and n, independently, is 1 or 2. In some embodiments, m is 2, X is O, n is 1, and Y is P(O)(ORa)(ORb), in which Ra can be H, and Rb can be 5-ethylidene-(3,4-dialkoxy)-furan-2-one.
Also within the scope of this invention is a method of preparing certain purine compounds of formula (I). The method includes reacting a compound of formula (III): 
with an alkyl-Xxe2x80x94(CH2) halide to obtain a compound of formula (IV): 
In formulae (III) and (IV), R1 is NH2 or OH; R2 is H or NH2; R3 is H or alkyl; and X is O, S, or NH; provided that if R1 is NH2, R2 is H; and if R1 is OH, R2 is NH2.
Unless specifically pointed out, alkyl, aryl, heteroaryl, cyclyl, heterocyclyl, adenine, guanine, cytosine, uracil, and thymine mentioned above include both substituted and unsubstituted moieties. The term xe2x80x9csubstitutedxe2x80x9d refers to one or more substituents (which may be the same or different), each replacing a hydrogen atom. Examples of substituents include, but are not limited to, halogen, cyano, nitro, hydroxyl, amino, mercapto, C1xcx9cC6 alkyl, C1xcx9cC6 alkenyl, C1xcx9cC6 alkynyl, aryl, heteroaryl, C4xcx9cC8 cyclyl, C4xcx9cC8 heterocyclyl, alkyloxy, aryloxy, alksulfanyl, arylsulfanyl, alkylamino, arylamino, dialkylamino, diarylamino, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkylcarboxyl, arylcarboxyl, heteroarylcarboxyl, alkyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbamido, arylcarbamido, heterocarbamido, alkylcarbamyl, arylcarbamyl, heterocarbamyl, wherein each of alkyl (including alk), alkenyl, aryl, heteroaryl, cyclyl, and heterocyclyl is optionally substituted with halogen, cyano, nitro, hydroxyl, amino, mercapto, C1xcx9cC6 alkyl, aryl, heteroaryl, alkyloxy, aryloxy, alkylcarbonyl, arylcarbonyl, alkylcarboxyl, arylcarboxyl, alkyloxycarbonyl, or aryloxycarbonyl.
The term xe2x80x9calkylxe2x80x9d refers to both linear and branched alkyl. The term xe2x80x9ccyclylxe2x80x9d refers to a hydrocarbon ring containing 4 to 8 carbons. The term xe2x80x9cheterocyclylxe2x80x9d refers to a ring containing 4 to 8 ring members that have at least one heteroatom (e.g., S, N, or O) as part of the ring. The term xe2x80x9carylxe2x80x9d refers to a hydrocarbon ring system having at least one aromatic ring. Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, and pyrenyl. The term xe2x80x9cheteroarylxe2x80x9d refers to a hydrocarbon ring system having at least one aromatic ring which contains at least one heteroatom such as O, N, or S. Examples of heteroaryl moieties include, but are not limited to, furyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridinyl, pyrimidinyl, quinazolinyl, and indolyl.
All of the purine compounds described above include the compounds themselves, as well as their salts. The salts, for example, can be formed between a positively charged substituent (e.g., amino) on a compound and an anion. Suitable anions include, but are not limited to, chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, and acetate. Likewise, a negatively charged substituent (e.g., carboxylate) on a compound can form a salt with a cation. Suitable cations include, but are not limited to, sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as teteramethylammonium ion.
In addition, some of the just-described purine compounds have one or more double bonds, or one or more asymmetric centers. Such compounds can occur as racemates, racemic mixtures, single enantiomers, individual diastereomers, diastereomeric mixtures, and cis- or trans- or E- or Z- double bond isomeric forms.
Exemplary purine compounds of formula (I) and (II) include: 
This invention also features a method of treating infection by virus. The method includes administering to a subject in need thereof an effective amount of a purine compound of formula (I) or formula (II) as described above. Examples of the viruses include DNA viruses such as herpesviridae (e.g., herpes simplex viruses) and retroviruses such as Moloney murine sarcoma viruses and human immunodeficiency viruses (e.g., human immunodeficiency viruses-1 or -2).
As used herein, the term xe2x80x9ctreating infectionxe2x80x9d refers to use of one or more purine compounds described above for preventing or treating infection by virus, or other disease states secondary to viral infection, e.g., cervical cancer induced by Papilovirus.
Also within the scope of this invention are a composition containing one or more of the aforementioned purine compounds for use in treating viral infection, and the use of such a composition for the manufacture of a medicament for infection treatment.
Other features or advantages of the present invention will be apparent from the following detailed description of several embodiments, and also from the appending claims.